EP0109441B1 - Humane-humane hybridomas für neoplasmen - Google Patents

Humane-humane hybridomas für neoplasmen Download PDF

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Publication number
EP0109441B1
EP0109441B1 EP83902157A EP83902157A EP0109441B1 EP 0109441 B1 EP0109441 B1 EP 0109441B1 EP 83902157 A EP83902157 A EP 83902157A EP 83902157 A EP83902157 A EP 83902157A EP 0109441 B1 EP0109441 B1 EP 0109441B1
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EP
European Patent Office
Prior art keywords
human
cells
monoclonal antibodies
antibodies
hybridoma
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP83902157A
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English (en)
French (fr)
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EP0109441A4 (de
EP0109441A1 (de
Inventor
Harold H. Handley
Mark C. Glassy
Hideaki Hagiwara
Yoshihide Hagiwara
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University of California
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University of California
University of California Berkeley
University of California San Diego UCSD
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Publication of EP0109441A4 publication Critical patent/EP0109441A4/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • the mammalian immune system has a matchless ability to produce molecules with specificity and avidity for a particular spatial and polar structure, as may be found with sequences of amino acids and sugars. For a long period of time, one was dependent upon producing antibodies employing the immune system in vivo .
  • the resulting polyclonal antibodies demonstrated high specificity for a specific antigen, but could not discriminate between various sites on the antigen and, furthermore, were a mixture of antibodies of varying specificity and avidity. Thus, one observed the averaging over the entire composition and not the properties of a specific antibody.
  • Monoclonal antibodies for these purposes desirably are specific for a particular type of cancer or subset of cancers, rather than being specific for a particular host cancer cell. it is therefore desirable to develop monoclonal antibodies which can be used in the diagnosis and treatment of human cancers.
  • GB-A-2 086 937 describes the production of human monoclonal antibodies from a hybridoma obtained by fusing a human myeloma cell with a human lymphocyte obtained from a patient contaminated with an active virus such as rabies, influenza, measles, vaccinia, polio, etc. There is no suggestion in this document that it would be possible to secure a monoclonal antibody of specificity such that it could distinguish neoplastic cells from human non-malignant cells.
  • the present invention provides human hybridomas capable of producing human monoclonal antibodies which distinguish human neoplastic cells from normal human cells, wherein said human hybridoma is obtainable by fusion of a B-lymphocyte from a draining lymph node of a human host having a neoplasia with a fusion partner for human cells, wherein said fusion partner is a human immortalized B-cell which itself does not secrete immunoglobulins; or human hybridomas derived therefrom.
  • the present invention also includes human monoclonal antibodies obtained from the hybridomas of the invention.
  • the antibodies of the invention, or fragments thereof are used to determine the presence of a neoplasm by combining a sample from a host suspected of having a neoplasm with the monoclonal antibodies or fragments thereof followed by the detecting of the presence of the binding of the monoclonal antibodies or fragments thereof.
  • a method for producing the human monoclonal antibodies of the invention by growing the hybridoma of the invention and recovering the antibodies produced by the hybridoma. Where necessary, these antibodies can be labeled.
  • human monoclonal antibodies or fragments thereof as described in the immediately preceding three paragraphs, for use in a method of treatment of the human body by therapy.
  • Human monoclonal antibodies specific for neoplastic cells from solid tumors are obtained from human x human fusions employing B lymphocytes, e.g., from lymph nodes draining a solid tumor. Particularly, lymph nodes are selected which appear to be active based on necrosis of tumor cells in the vicinity of the lymph node in an immunocompetent host.
  • the draining lymph node(s) may be isolated in conjunction with a variety of human tissue, e.g., cervix, mammary, colon, lungs, prostate, skin, etc. Of particular interest are lymph nodes from the spinal area.
  • the fusion partner may be any convenient immortalized B-cell, which does not secrete immunoglobulins, individual chains or fragments thereof, can be selected against, as with HAT medium, and desirably has a high fusion efficiency.
  • Illustrative fusion partners are UC729-6, J-4 (SKO-007), and GM1500 6TG-A12.
  • the fusions may be performed as described in the literature employing PEG1500 as fusogen, plating the cells in HAT medium in a plurality of wells and then screening supernatants in the viable cell wells for antibodies of interest. Wells positive for reactivity are then cloned by limiting dilution and expanded.
  • CLNH5 and CLNH11 are obtained by fusion between the fusion partner UC729-6 with lymphocytes from lymph node cells of a patient having cervical cancer.
  • UC729-6 was deposited on 25 March 1981 at the A.T.C.C. Maryland, USA, with Accession No. CRL 8061.
  • the lymphocytes employed for fusion were from a draining lymph node from the spinal area and peripheral blood lymphocytes from a patient having cervical carcinoma.
  • the fusion is performed by combining the patient's lymphocytes from the lymph node with the fusion partner UC729-6 at a ratio of about 2:1 in a solution of about 35% polyethylene glycol in HEPES buffered RPMI 1640.
  • the mixture of cells is then suspended in appropriate selective medium, particularly HAT medium containing about 10% fetal bovine serum, placed in wells at about 105 cells per well and a sufficient time permitted for the cells to grow.
  • the selective medium is replaced from time to time.
  • Wells from the above fusion provided clones specifically reactive with the cervical cancer cells of the host patient which were designated CLNH5 and 11. These wells provided human IgM and IgG monoclonal antibodies, respectively, which react with antigen found on a variety of cervical carcinomas and other tumor cell lines, e.g., small cell carcinoma of the lung, but not with normal tissues and normal cell lines, which were tested.
  • hybridomas and monoclonal antibodies can find use in a variety of ways, particularly as sources of genetic material, as reagents, and as precursors to products which find use as reagents.
  • the subject hybridomas may be used as a source for genetic material.
  • the subject hybridomas may be fused with other fusion partners to provide novel hybridomas having the same secretory capabilities as CLNH5 and 11 to provide antibodies having the same specificity.
  • Such fusions may result in the production of antibodies having different heavy chains so as to provide the other classes or subclasses of antibodies, e.g., G, A or M.
  • the hybridoma may also be used as a source of DNA, which by hybrid DNA technology, the genes may be excised, introduced into a lymphoma for production of the mature antibodies.
  • the monoclonal antibodies can be used in a variety of ways, both in vivo and in vitro diagnosis, as well as in therapy.
  • the antibodies will be labeled with a compound which imparts a desired property to the antibodies, such as providing a detectable signal, providing cytotoxicity, providing for localized electromagnetic radiation, or the like.
  • Labels may include radionuclides, enzymes, fluorescers, toxins or the cytotoxic fragment of toxins, particles, metals, metalloids, etc.
  • the antibodies may be incorporated in liposome membranes or modified with lipids, so as to be incorporated in such membranes.
  • the antibodies by themselves or labeled, may be used in in vitro diagnosis for measuring the presence of antigens associated with a neoplasm such as cervical cancer, for in vivo diagnosis for introduction into a host, e.g., intravenously, in a physiologically acceptable carrier, e.g., PBS, or may be introduced for therapeutic purposes in the same manner.
  • a physiologically acceptable carrier e.g., PBS
  • the antibodies by themselves or labeled, may also be used for treating a neoplasm in human host such as cervical carcinoma, prostate tumor, colon carcinoma, lung cancer, breast cancer and melanoma.
  • the antibodies of this invention are easily soluble in physiological saline, and therefore can be injected intravenously or intramuscularly as a saline solution or a drip.
  • the antibodies of the invention can be used in the form of an ointment or suppository.
  • Lymph nodes were teased with nugent forceps in RPMI 1640 media and isolated lymphocytes were cultured overnight at 37°C and 5% CO2 in RPMI 1640 with 10% fetal calf serum (FCS) and 2mM L-glutamine. Lymphocytes were counted and mixed at a ratio of 2:1 with the human lymphoblastoid B cell line UC729-6 (Handley and Royston. 1982, in Hybridomas in Cancer Diagnosis and Treatment, eds. Mitchell and Oettgen, pp.
  • Hybridoma culture fluids were precipitated with 50% ammonium sulfate and crude Ig fractions collected. The precipitates were dissolved in phusiological saline and purified by affinity chromatography using S - aureus Protein A-bound Sepharose with IgC and Sepharose-(sheep anti(humanIgM) antibody) with IgM. From 1L of the culture fluid of CLNH5, 2.2mg IgM was obtained, while from 1L of the culture fluid of CLNH11, 3.0mg IgG was obtained.
  • Table 1 outlines the results of the fusion attempting to produce anti-SCCC (squamous cell carcinoma of cervix) human MoAbs.
  • Hybridomas CLNH5 and CLNH11 were cloned and expanded when found to react with the cervical carcinoma cell lines, CaSki and Hela.
  • Antibody (IgM) secreted by CLNH5 shows positive reactivity with carcinomas of the cervix (CaSki, Hela), lung (T293, Calu-1, and SK-MES-1), melanoma (SK-MEL-28), and prostate (LnCap) and was negative for normal fibroblasts, T lymphocytes and peripheral blood lymphocytes.
  • Antibody (IgG) secreted by CLNH11 shows positive reactivity with carcinomas of the cervix (CaSki, Hela), prostate (PC-3), breast (ZR-76-1), colon (COLO-205) and melanoma (G-361) and was negative for normal fibroblasts (WI . 38 and MRC-9), T. lymphocytes and peripheral blood lymphocytes.
  • the cytobiochemical properties of the hybridomas of the present invention are shown below.
  • hybridoma CLNH5 can be proliferated in HAT medium (medium containing hypoxanthine, amethopterin and thymidine).
  • the above hybridoma CLNH11 can be proliferated in HAT medium.
  • the relative DNA content (the ratio to the DNA content of normal human lymphocytes) was determined by a method which comprises dyeing the hybridoma and then separating and analyzing it by a cytofluorometer.
  • the subject monoclonal antibodies are useful for the diagnosing, imaging and potentially for treating cervical carcinoma as well as other reactive tumors. Because of the specificity of the monoclonal antibodies over a rnage of cervical carcinomas from different hosts, the subject antibodies can be used in different hosts, rather than solely with the host source of the antigen. Because the subject antibodies are human, they are less likely to produce a significant immune response when employed in in vivo diagnosis or therapy.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Claims (15)

  1. Humane Hybridome, die zur Bildung von humanen monoklonalen Antikörpern fähig sind, welche humane neoplastische Zellen von normalen humanen Zellen unterscheiden, worin dieses humane Hybridom durch eine Fusion eines B-Lymphozyten aus einer Lymphknotendrainage eines menschlichen Wirts, der ein Neoplasma aufweist, mit einem Fusionspartner für humane Zellen erhalten werden kann, worin dieser Fusionspartner eine humane immortalisierte B-Zelle ist, die ihrerseits keine Immunglobuline sekretiert, oder hiervon abstammende humane Hybridome.
  2. Humane Hybridome CLNH5 oder CLNH11 nach Anspruch 1.
  3. Humane monoklonale Antikörper, die von humanen Hybridomen nach einem der Ansprüche 1 oder 2 erhalten wurden.
  4. Humane monoklonale Antikörper nach Anspruch 3, worin die neoplastischen Zellen Zellen solider Tumoren sind.
  5. Humane monoklonale Antikörper nach Anspruch 3, worin die neoplastischen Zellen Prostatakarzinomzellen, kleinzellige Lungenkarzinomzellen, Zervixkarzinomzellen, Kolonkarzinomzellen oder Melanomzellen sind.
  6. Humane monoklonale Antikörper nach Anspruch 3, worin die neoplastischen Zellen Zervixkarzinomzellen sind.
  7. Humane monoklonale Antikörper nach einem der Ansprüche 3 bis 6 oder Fragmente hiervon, die mit einer Markierung markiert sind, die ein detektierbares Signal liefern kann.
  8. Humane monoklonale Antikörper nach Anspruch 7 oder Fragmente hiervon, worin diese Markierung ein Radionuklid ist.
  9. Humane monoklonale Antikörper nach einem der Ansprüche 3 bis 6 oder Fragmente hiervon, die mit einem Toxin markiert sind.
  10. Verwendung der monoklonalen Antikörper oder der Fragmente hiervon nach einem der Ansprüche 3 bis 9, um das Vorkommen eines Neoplasmas zu bestimmen, welche umfaßt:
    - Zusammenbringen einer Probe eines Wirts, bei dem ein Neoplasma vermutet wird, mit den monoklonalen Antikörpern oder Fragmenten hiervon und
    - Detektion der Bindung dieser monoklonalen Antikörper oder Fragmente hiervon.
  11. Verwendung der monoklonalen Antikörper nach Anspruch 10, worin diese Probe ein Wirtsgewebe ist.
  12. Verwendung der monoklonalen Antikörper nach Anspruch 10 oder 11, worin dieses Neoplasma ein solider Tumor ist.
  13. Verwendung der monoklonalen Antikörper nach Anspruch 12, worin dieser solide Tumor ein Zervixkarzinom, Prostatatumor, Kolonkarzinom, Lungenkrebs, Brustkrebs oder Melanom ist.
  14. Verfahren zur Herstellung von humanen monoklonalen Antikörpern nach einem der Ansprüche 3 bis 9, das die Anzucht eines Hybridoms nach Anspruch 1 oder 2 und die Gewinnung der von diesem Hybridom gebildeten Antikörper, und falls gewünscht, die Markierung der Antikörper umfaßt.
  15. Humane monoklonale Antikörper oder Fragmente hiervon nach einem der Ansprüche 3 bis 9 zur Verwendung in einem Behandlungsverfahren des menschlichen Körpers bei einer Therapie.
EP83902157A 1982-05-21 1983-05-20 Humane-humane hybridomas für neoplasmen Expired - Lifetime EP0109441B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP84843/82 1982-05-21
JP57084843A JPS58201994A (ja) 1982-05-21 1982-05-21 抗原特異的ヒト免疫グロブリンの生産方法
PCT/US1983/000781 WO1983004313A1 (en) 1982-05-21 1983-05-20 Human-human hybridomas for neoplasms

Publications (3)

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EP0109441A1 EP0109441A1 (de) 1984-05-30
EP0109441A4 EP0109441A4 (de) 1986-09-22
EP0109441B1 true EP0109441B1 (de) 1994-11-17

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EP83902157A Expired - Lifetime EP0109441B1 (de) 1982-05-21 1983-05-20 Humane-humane hybridomas für neoplasmen

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EP (1) EP0109441B1 (de)
JP (2) JPS58201994A (de)
AT (1) ATE114189T1 (de)
AU (1) AU560595B2 (de)
CZ (1) CZ280677B6 (de)
DE (1) DE3382764T2 (de)
DK (1) DK164510C (de)
FI (1) FI86077C (de)
HU (1) HU190908B (de)
IN (1) IN157982B (de)
SK (1) SK279249B6 (de)
WO (1) WO1983004313A1 (de)
ZA (1) ZA833686B (de)

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AU560595B2 (en) 1987-04-09
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DK25084A (da) 1984-01-20
EP0109441A4 (de) 1986-09-22
IN157982B (de) 1986-08-09
SK356683A3 (en) 1998-08-05
ATE114189T1 (de) 1994-12-15
HU190908B (en) 1986-12-28
AU1772983A (en) 1983-12-16
JPS58201994A (ja) 1983-11-25
DK164510B (da) 1992-07-06
DK25084D0 (da) 1984-01-20
FI840219L (fi) 1984-01-19
DE3382764T2 (de) 1995-03-16
EP0109441A1 (de) 1984-05-30
JPS60501359A (ja) 1985-08-22
FI86077B (fi) 1992-03-31
JPH0159878B2 (de) 1989-12-20
WO1983004313A1 (en) 1983-12-08
SK279249B6 (sk) 1998-08-05
CZ280677B6 (cs) 1996-04-17

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